Zuo Yunyan, Xue Jiahui, Wen Haixia, Zhan Lixuan, Chen Meiyan, Sun Weiwen, Xu En
Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
Department of Neurology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China.
Commun Biol. 2025 Feb 11;8(1):214. doi: 10.1038/s42003-025-07644-5.
Hypoxic postconditioning (HPC) was reported to stabilize nuclear β-catenin by inhibiting lysine (K)-specific demethylase 2 A (KDM2A) in hippocampal CA1 against transient global cerebral ischemia (tGCI). Herein we investigate how HPC inhibits the K48-linked poly-ubiquitination (K48-Ub)-related degradation of nuclear β-catenin in CA1 after tGCI. We confirmed that SCF complex targets nuclear β-catenin for degradation via ubiquitin proteasome pathway in vitro. HPC reduced SCF complex and the K48-Ub of β-catenin, and increased ubiquitin-specific peptidase 22 (USP22) in nucleus after tGCI. Furthermore, KDM2A knockdown decreased the K48-Ub of nuclear β-catenin and nuclear β-catenin-SCF complex interaction after tGCI. Moreover, β-catenin knockdown suppressed nuclear survivin expression and attenuated neuroprotection induced by HPC. In contrast, the overexpression of USP22 promoted nuclear β-catenin deubiquitination and enhanced the neuroprotective effects offered by HPC. Taken together, this study supports that HPC downregulated the K48-Ub of nuclear β-catenin through suppressing SCF and increasing USP22, thereby inducing cerebral ischemic tolerance.
据报道，缺氧后适应（HPC）通过抑制海马CA1区赖氨酸（K）特异性去甲基化酶2A（KDM2A）来稳定核β-连环蛋白，以对抗短暂性全脑缺血（tGCI）。在此，我们研究HPC如何抑制tGCI后CA1区核β-连环蛋白的K48连接的多聚泛素化（K48-Ub）相关降解。我们证实在体外SCF复合物通过泛素蛋白酶体途径靶向核β-连环蛋白进行降解。tGCI后，HPC降低了SCF复合物和β-连环蛋白的K48-Ub，并增加了细胞核中泛素特异性肽酶22（USP22）。此外，KDM2A基因敲低降低了tGCI后核β-连环蛋白的K48-Ub以及核β-连环蛋白与SCF复合物的相互作用。而且，β-连环蛋白基因敲低抑制了核存活素表达，并减弱了HPC诱导的神经保护作用。相反，USP22的过表达促进了核β-连环蛋白的去泛素化，并增强了HPC提供的神经保护作用。综上所述，本研究支持HPC通过抑制SCF并增加USP22来下调核β-连环蛋白的K48-Ub，从而诱导脑缺血耐受性。
